Principal Investigator/Program Director (Last, first, middle): Tucker, Philip, W. Abstract This grant over the past 24 years has supported a wide range of studies focused broadly on immunoglobulin gene expression. This renewal concentrates on the forkhead transcription factor, Foxp1. Conventional Foxp1 knockout (KO) leads to mid-gestation cardiovascular dysfunction and lethality. RAG2-/- reconstitution studies demonstrated an intrinsic block of B cell development at the pro-B stage. Thymic development in Foxp1-/--reconstituted RAG-/- mice is normal, but peripheral CD4 T cell subsets and functions are deregulated. We propose to generation conditional Foxp1 knockout mice to study the effects of intrinsic Foxp1 deficiency on B cell and T cell development. We propose to identify Foxp1 target genes to define pathways and mechanisms by which Foxp1 contributes to normal and malignant B cell development. These studies hold clinical relevance in that Foxp1 over- expression is a hallmark of the most aggressive and worst prognostic subset of diffuse large B cell lymphoma. Project Description Page 6